Incident Type 2 Diabetes Duration and Cancer Risk

A Prospective Study in Two US Cohorts

Yang Hu, ScD; Xuehong Zhang, MD, ScD; Yanan Ma, PhD; Chen Yuan, ScD; Molin Wang, PhD; Kana Wu, MD, PhD; Fred K. Tabung, MSPH, PhD; Deirdre Tobias, ScD; Frank B. Hu, MD, PhD; Edward Giovannucci, MD, ScD; Mingyang Song, MD, ScD


J Natl Cancer Inst. 2021;113(4):381-389. 

In This Article

Abstract and Introduction


Background: The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood.

Methods: We prospectively followed for cancer incidence 113 429 women in the Nurses' Health Study (1978–2014) and 45 604 men in the Health Professionals Follow-up Study (1988–2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records.

Results: In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1–6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1–8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1–10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years.

Conclusions: Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.


The US Center for Disease Control estimated that more than 34 million Americans had diabetes mellitus in 2020, accounting for 10.5% of the US population.[1] A growing body of evidence indicates a close link between the presence of type 2 diabetes mellitus (T2D) and risk of certain types of cancer.[2] However, few previous studies simultaneously addressed multiple methodological challenges in the associations between T2D and cancer risk, including ascertainment bias because of more frequent screening following T2D diagnosis, reverse causality (such as pancreatic cancer), and influence of cancer screening.[3] Moreover, the evidence regarding the associations of T2D with other cancers such as kidney and lung cancer remains inconclusive.[2] In addition, the association between T2D duration and cancer risk remains poorly understood. Specifically, little is known about whether the increased cancer risk following T2D diagnosis would persist in patients with longer T2D duration or gradually diminish over time as endogenous production of insulin decreases.[4] Also, whether such duration-related patterns vary by cancer types is yet to be determined. Characterizing the cancer risk trajectory following T2D diagnosis not only is critical to assess the long-term influence of diabetes on cancer incidence but also directly pertains to the assessment of cancer latency period, an important factor to elucidate the role of T2D in tumorigenesis.

The current study aimed to evaluate the association between incident T2D, T2D duration, and cancer incidence for multiple composite cancer outcomes as well as individual cancers while addressing aforementioned methodological issues. To gain mechanistic insights, we also assessed plasma levels of C-peptide and HbA1c, 2 most commonly used clinical measures for endogenous insulin secretion and long-term blood glucose concentration,[5,6] respectively, according to diabetes duration. We leveraged data from Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS), 2 large well-characterized cohort studies with disease status and lifestyle factors repeatedly assessed over 3 decades of follow-up.